Activation of the calpain system might contribute to the impairment of synaptic transmission in Alzheimer's Disease (AD). Calpains regulate the function of many proteins by limited proteolysis and initiate the complete degradation of other proteins. In particular, they modulate processes that govern the function and metabolism of proteins key to the pathogenesis of AD, including tau and amyloid precursor protein. Based on the observation that the protease inhibitors, E64 and BDA-410, are capable of blocking the impairment of synaptic function and cognition in an amyloid-depositing mouse model of AD, the mAPP/mPS1 mouse, we will identify molecules that re-establish normal cognition in mAPP/mPS1 animals by inhibiting calpains. Our approach is to combine expertise in organic chemistry to generate new molecules acting on the signaling pathway with experience in neurobiology to test these compounds at multiple levels including neuronal cultures and in vivo animals. This strategy offers the advantage of screening novel drugs in a less costly system (cell cultures), and of determining whether they re-establish normal learning and memory in an in vivo complex neuronal system that is used as an AD model (the whole animal). The following aims will be addressed: a) to identify new calpain inhibitors and optimize their efficacy for synaptic rescue;b) to screen new calpain inhibitors by selecting compounds that rescue synaptic dysfunction in mAPP/mPS1 mice;c) to further screen calpain inhibitors selected through tests on synaptic function to examine whether they prevent cognitive abnormalities in adult mAPP/mPS1 mice. The whole project will be organized in clear milestones with objective success/failure criteria and GO/NOGO decision points within a collaborative effort with the NIA staff, clinicians and clinical trials experts participating to the annual meeting set by the NIA. The final phase of this work will go beyond the support requested in this application, but will include the crafting of a partnership with industry to bring drugs to patients. On the completion of these studies we will identify new therapeutic agents ameliorating memory loss in AD and other neurodegenerative diseases characterized by elevated levels of amyloid through inhibition of calpain enzymatic activity.